The 3PAs: An Update on the Association of Pheochromocytomas, Paragangliomas, and Pituitary Tumors

Abstract

Supplementary material for this article is available online at http://www.thieme-connect.de/products. ABStr AC tPituitary adenomas (PA) and pheochromocytomas/paragangliomas (PHEO/PGL) are rare tumors. Although they may co-exist by coincidence, there is mounting evidence that genes predisposing in PHEO/PGL development, may play a role in pituitary tumorigenesis. In 2012, we described a GH-secreting PA caused by an SDHD mutation in a patient with familial PGLs and found loss of heterozygosity at the SDHD locus in the pituitary tumor, along with increased hypoxia-inducible factor 1α (HIF-1α) levels. Additional patients with PAs and SDHx defects have since been reported. Overall, prevalence of SDHx mutations in PA is very rare (0.3-1.8 % in unselected cases) but we and others have identified several cases of PAs with PHEOs/ PGLs, like our original report, a condition which we termed the 3 P association (3PAs). Interestingly, when 3PAs is found in the sporadic setting, no SDHx defects were identified, whereas in familial PGLs, SDHx mutations were identified in 62.5-75 % of the reported cases. Hence, pituitary surveillance is recommended among patients with SDHx defects. It is possible that the SDHx germline mutation-negative 3PAs cases may be due to another gene, epigenetic changes, mutations in modifier genes, mosaicism, somatic mutations, pituitary hyperplasia due to ectopic hypothalamic hormone secretion or a coincidence. PA in 3PAs are mainly macroadenomas, more aggressive, more resistant to somatostatin analogues, and often require surgery. Using the Sdhb + / − mouse model, we showed that hyperplasia may be the first abnormality in tumorigenesis as initial response to pseudohypoxia. We also propose surveillance and follow-up approach of patients presenting with this association.

A review of the tumour spectrum of germline succinate dehydrogenase gene mutations: Beyond phaeochromocytoma and paraganglioma

“…Unselected cohorts of PAs have relatively low rates of SDH deficiency and unpublished data from our centre has shown 1 case in 150 unselected surgical PA cases (0.7%). This is in keeping with published data suggesting a prevalence of 0.3%‐1.8% in unselected PA cases 43,44 . A recent study reviewing the frequency of germline genetic mutations in a select cohort of patients with a history of PC, PGL and pituitary tumours, demonstrated that SDHx mutations were the most common germline mutation observed (19/82 cases (23%)) 44 …”

“…Vacuolated clear cytoplasm has been documented as a characteristic histological hallmark of SDH‐deficient PA 45 and it has been hypothesized these may be by‐products of autophagy of abnormal mitochondria 44 (Figure 1). Definitive description of the SDH‐deficient PA clinical phenotype is difficult given the low number of reported cases thus far, but the majority of the reported PAs are of PIT‐1 lineage (lactotropinomas or somatotropinomas) although isolated reports of silent gonadotroph adenomas and corticotropinomas have been documented 44 . There is no clear genotype‐phenotype correlation for SDH‐deficient PA and mutations in all four SDHx subunit genes have been reported to associate with the presence of these tumours 44 .…”

“…In addition, the above‐mentioned imaging protocol will provide a good survey for extra adrenal PGL and PC as well as renal tumours and wtGIST. Although the incidence of SDHx mutations in sporadic PAs is low, the frequency of SDHx mutations is significantly higher in cohorts of patients with familial PPGL 44 . Although it has been suggested that screening for PAs is considered, as yet, there is not an adequate evidence base for the clinical utility and cost‐effectiveness of surveillance and therefore if it is offered it would be best performed as part of a clinical trial or service evaluation.…”

Medical Treatment of Pituitary Adenomas: A Celebration of Endocrinology (and Oncology)!

“…The article follows a number of recent articles in our journal on the treatment and genetics of pituitary tumors; some are listed here as examples [4][5][6][7].…”

Genetic Testing in Pituitary Adenomas: What, How, and In Whom?

“…One further syndromic situation of growing interest is the potential for a pituitary adenoma, pheochromocytoma/paraganglioma association (3PA) 14 . In individuals or kindreds presenting with 3PA, a number of mutated genes have been identified, including the succinate dehydrogenase subunit genes (SDHx); recently, mutations and intragenic deletions in MAX have also been implicated in 3PA 15 .…”